tbuckley/cabot-search huggingface dataset:
Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adults
Authors: Saskia C van der Boor, Merel J Smit, Stijn W van Beek, Jordache Ramjith, Karina Teelen, Marga van de Vegte-Bolmer, Geert-Jan van Gemert, Peter Pickkers, Yimin Wu, Emily Locke, Shwu-Maan Lee, John Aponte, C Richter King, Ashley J Birkett, Kazutoyo Miura, Morolayo A Ayorinde, Robert W Sauerwein, Rob ter Heine, Christian F Ockenhouse, Teun Bousema, Matthijs M Jore, Matthew B B McCall
Journal: The Lancet Infectious Diseases (2022)

BackgroundMalaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants.MethodsIn this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689.FindingsBetween Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 μg/mL (95% CI 1·9–2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136–193) following a single intravenous 10 mg/kg dose.InterpretationTB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season.FundingPATH's Malaria Vaccine Initiative.
Non-fatal overdose risk during and after opioid agonist treatment: A primary care cohort study with linked hospitalisation and mortality records
Authors: Eleni Domzaridou, Matthew J. Carr, Roger T. Webb, Tim Millar, Darren M. Ashcroft
Journal: The Lancet Regional Health - Europe (2022)

The initiation and cessation of opioid agonist treatment (OAT) have both been associated with elevated risk of fatal overdose. We examined risk of non-fatal overdose during OAT initiation and cessation and specifically between methadone versus buprenorphine recipients.We utilised primary care electronic health records from the Clinical Practice Research Datalink to delineate a study cohort of adults aged 18-64 who were prescribed OAT between Jan 1, 1998 and Dec 31, 2017. These records were linked to hospitalisation, mortality records and patient neighbourhood and practice-level Index of Multiple Deprivation quintiles. With inverse probability treatment weights applied and negative binomial regression models we estimated incidence rate ratios for hospital admissions among patients who experienced multiple overdoses.A total of 20898 patients were prescribed methadone or buprenorphine over 83856 person-years of follow-up. Compared with periods in treatment, patients not in treatment were 51% more likely to experience a non-fatal overdose that required hospitalisation (weighted rate ratio, wRR 1·51; 95% CI 1·42, 1·60), especially during the four weeks of OAT initiation (5·59; 5·31, 5·89) and following cessation (13·39; 12·78, 14·03). The wRR of overdose during (0·37; 0·34, 0·39) and after treatment (0·36; 0·34, 0·38) favoured buprenorphine compared to methadone.OAT is associated with decreased non-fatal overdose risk. Buprenorphine may act more protectively than methadone, especially during the first four weeks of treatment.National Institute for Health and Care Research (NIHR) Greater Manchester Patient Safety Translational Research Centre (PSTRC-2016-003).
Comparative neutralisation profile of SARS-CoV-2 omicron subvariants BA.2.75 and BA.5
Authors: Chee-Wah Tan, Beng-Lee Lim, Barnaby E Young, Aileen Ying-Yan Yeoh, Chee-Fu Yung, Wee-Chee Yap, Thomas Althaus, Wan-Ni Chia, Feng Zhu, David Chien Lye, Lin-Fa Wang
Journal: The Lancet Microbe (2022)
Interaction of ARRDC4 With GLUT1 Mediates Metabolic Stress in the Ischemic Heart
Authors: Yoshinobu Nakayama, Nobuhiro Mukai, Geri Kreitzer, Parth Patwari, Jun Yoshioka
Journal: Circulation Research (2022)

An ancient family of arrestin-fold proteins, termed alpha-arrestins, may have conserved roles in regulating nutrient transporter trafficking and cellular metabolism as adaptor proteins. One alpha-arrestin, TXNIP (thioredoxin-interacting protein), is known to regulate myocardial glucose uptake. However, the in vivo role of the related alpha-arrestin, ARRDC4 (arrestin domain-containing protein 4), is unknown.We first tested whether interaction with GLUTs (glucose transporters) is a conserved function of the mammalian alpha-arrestins. To define the in vivo function of ARRDC4, we generated and characterized a novel Arrdc4 knockout (KO) mouse model. We then analyzed the molecular interaction between arrestin domains and the basal GLUT1.ARRDC4 binds to GLUT1, induces its endocytosis, and blocks cellular glucose uptake in cardiomyocytes. Despite the closely shared protein structure, ARRDC4 and its homologue TXNIP operate by distinct molecular pathways. Unlike TXNIP, ARRDC4 does not increase oxidative stress. Instead, ARRDC4 uniquely mediates cardiomyocyte death through its effects on glucose deprivation and endoplasmic reticulum stress. At baseline, Arrdc4-KO mice have mild fasting hypoglycemia. Arrdc4-KO hearts exhibit a robust increase in myocardial glucose uptake and glycogen storage. Accordingly, deletion of Arrdc4 improves energy homeostasis during ischemia and protects cardiomyocytes against myocardial infarction. Furthermore, structure-function analyses of the interaction of ARRDC4 with GLUT1 using both scanning mutagenesis and deep-learning Artificial Intelligence identify specific residues in the C-terminal arrestin-fold domain as the interaction interface that regulates GLUT1 function, revealing a new molecular target for potential therapeutic intervention against myocardial ischemia.These results uncover a new mechanism of ischemic injury in which ARRDC4 drives glucose deprivation-induced endoplasmic reticulum stress leading to cardiomyocyte death. Our findings establish ARRDC4 as a new scaffold protein for GLUT1 that regulates cardiac metabolism in response to ischemia and provide insight into the therapeutic strategy for ischemic heart disease.
Wet adhesive hydrogel cardiac patch loaded with anti-oxidative, autophagy-regulating molecule capsules and MSCs for restoring infarcted myocardium
Authors: Tengling Wu, Xiaoping Zhang, Yang Liu, Chunyan Cui, Yage Sun, Wenguang Liu
Journal: Bioactive Materials (2022)

Hydrogel patch-based stem cell transplantation and microenvironment-regulating drug delivery strategy is promising for the treatment of myocardial infarction (MI). However, the low retention of cells and drugs limits their therapeutic efficacies. Here, we propose a prefixed sponge carpet strategy, that is, aldehyde-dextran sponge (ODS) loading anti-oxidative/autophagy-regulating molecular capsules of 2-hydroxy-β-cyclodextrin@resveratrol (HP-β-CD@Res) is first bonded to the rat's heart via capillary removal of interfacial water from the tissue surface, and the subsequent Schiff base reaction between the aldehyde groups on ODS and amino groups on myocardium tissue. Then, an aqueous biocompatible hydrazided hyaluronic acid (HHA) solution encapsulating mesenchymal stem cells (MSCs) is impregnated into the anchored carpet to form HHA@ODS@HP-β-CD@Res hydrogel in situ via click reaction, thus prolonging the in vivo retention time of therapeutic drug and cells. Importantly, the HHA added to outer surface consumes the remaining aldehydes to contribute to nonsticky top surface, avoiding adhesion to other tissues. The embedded HP-β-CD@Res molecular capsules with antioxidant and autophagy regulation bioactivities can considerably improve cardiac microenvironment, reduce cardiomyocyte apoptosis, and enhance the survival of transplanted MSCs, thereby promoting cardiac repair by facilitating angiogenesis and reducing cardiac fibrosis.
POS0211 ASSOCIATION BETWEEN CARDIOVASCULAR OUTCOME AND RHEUMATOID ARTHRITIS: NATIONWIDE POPULATION-BASED COHORT STUDY
Authors: S. Kang, K. D. Han, S. Lee, Y. Eun, H. S. Cha, E. M. Koh, J. Lee, H. Kim
Journal: Annals of the Rheumatic Diseases (2022)

Background Many studies have shown increased risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA). Despite a growing burden posed by CVD in RA patients, large scale studies which examined the association between characteristic of RA patients and CVD risks, and studies which adjusted for various confounding factors are lacking. Objectives This study aimed to investigate the association between CVD risk and RA in large-scale, nationwide cohort of Korean population, and to examine which characteristics of RA patients are associated with increased CVD risk. Methods We enrolled 136,469 patients with RA who participated in national health examinations within 2 years of RA diagnosis between 2010 and 2017 and non-RA controls matched by age and sex (n= 682,345). The cohort was followed until the end of 2019. The outcome was occurrence of myocardial infarction (MI) or stroke. MI was defined as one hospitalization or two outpatient visit with ICD-10-CM codes I21 or I22. Stroke was defined as one hospitalization with ICD-10-CM codes I63 or I64 and a claim for brain imaging (CT or MRI). The Cox proportional hazard model and Kaplan Meier curve were used for the analysis. Results Mean follow up duration was 4.7 years. The incidence rate of CVD was higher in RA group than control (MI: 3.20 vs 2.08; stroke: 2.84 vs 2.33 per 1,000 person-years). The risk of CVD was higher in RA patients. (MI: adjusted HR 1.54, 95% CI 1.46-1.61; Stroke: adjusted HR 1.22, 95% CI 1.16-1.28). The association between RA and CVD was prominent in female (MI: adjusted HR 1.41 in male, 1.60 in female, p for interaction = 0.0293; Stroke: adjusted HR 1.13 in male, 1.27 in female, p for interaction = 0.03) and younger-age subgroups (MI: adjusted HR 2.9 in &lt;40 years, 1.52 in 40-64 years, 1.51 in ≥65 years, p for interaction&lt;0.0001; Stroke: adjusted HR 2.35 in &lt;40 years, 1.21 in 40-64 years, 1.21 in ≥65 years, p for interaction = 0.0100) after adjusting for confounding variables. The association between RA and risk of MI was significant in those without DM. (adjusted HR 1.30 in DM, 1.61 in non-DM, p for interaction = 0.0005) Conclusion RA patients had increased risk of CVD events compared to age- and sex-matched control group, and this association was stronger in female and younger-age subgroups. Therefore appropriate screening for CVD would be important in all RA patients including female and younger patients. Disclosure of Interests None declared
POS0021 CHANGES OF GUT MICROBIOTA IN CONNECTIVE TISSUE DISEASE AND ITS RELATIONSHIP WITH LYMPHOCYTE SUBSETS AND CYTOKINES
Authors: J. Q. Zhang, J. Luo, Q. Y. Su, J. Qiao, S. X. Zhang, X. Li, C. Wang
Journal: Annals of the Rheumatic Diseases (2022)

Background Connective tissue disease (CTD) is a group of autoimmune diseases characterized by the damage of connective tissue components in various parts of the body, which involved multiple organs and systems. Dysbiosis in the gut microbiome is associated with various autoimmune diseases such as CTD. Objectives To explore the characters of gut microbiota and their relationship with peripheral lymphocyte subsets and cytokines in patients with CTD. Methods Stool samples were collected from 63 CTD patients and 63 age- and sex-matched healthy controls(HCs). Microbial genomes were extracted for 16S rRNA gene sequencing. Gut microbiota characters (alpha diversity, beta diversity, and microbial composition) were analysed by R (version 4.0.1). Peripheral lymphocyte subsets were assessed by flow cytometry. Pearson correlation analysis was used to detect the correlation between the relative abundance of genus in the sample and the activity index; correlations with p &lt; 0.05 were considered significant. Results Shannon and Simpson index revealed a decreased alpha diversity in CTD compared with that of HCs (p &lt; 0.05), though not significantly difference in ACE and Chao1 parameters (p &gt; 0.05, Figure 1A). Bray curtis distance-based beta-diversity analysis indicated significant differences in microbial communities between CTD and HCs (p = 0.0014, ANOSIM, Figure 1B). At the genus level, CTD patients had higher abundances of Terrisporobacter (p&lt;0.01), Paraprevotella (p&lt;0.01), CAG−352 (p&lt;0.01), et al. but lower abundances of Streptococcus (p&lt;0.01), Pseudomonas (p&lt;0.01), Bacteroides(p&lt;0.01), et al (Figure 1D). IgM was positively correlated with Lactococcus (p&lt;0.05), Family_XIII_AD3011_group (p&lt;0.05), Streptococcus (p&lt;0.05). Th17 was positively correlated with Pseudomonas (p&lt;0.01). Th2 was positively correlated with Christensenellaceae_R−7_group (p&lt;0.001), UCG−010 (p&lt;0.001) was positively correlated. Treg and Th2 were positively correlated with Christensenellaceae_R−7_group (p&lt;0.01), UCG−010 (p&lt;0.01). Treg was positively correlated with Lachnoclostridium (p&lt;0.05) (Figure 1E). Conclusion Pattients with CTD had disbiosis of gut microbiota charaterized by impared diversity and abnomal composition,which was closely correlated with peripheral lymphocyte subsets. References [1]Laura Ghezzi,Claudia Cantoni,Gabriela V Pinget,et al.Targeting the gut to treat multiple sclerosis.J Clin Invest.2021 Jul 1;131(13):e143774. doi: 10.1172/JCI143774. [2]Yoshihiko Tomofuji,Toshihiro Kishikawa,Yuichi Maeda,et al.Whole gut virome analysis of 476 Japanese revealed a link between phage and autoimmune disease.Ann Rheum Dis. 2022 Feb;81(2):278-288. doi: 10.1136/annrheumdis-2021-221267. Epub 2021 Dec 8. Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 82001740). Disclosure of Interests None declared
POS0245 PROTEIN PROFILING IN PRE-SYMPTOMATIC ANCA-ASSOCIATED VASCULITIS INDIVIDUALS.
Authors: M. Brink, E. Berglin, A. J. Mohammad, A. Alexeyenko, K. Lejon, S. Rantapää Dahlqvist
Journal: Annals of the Rheumatic Diseases (2022)

Background Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare chronic relapsing condition, with unknown etiology. Objectives This study was undertaken to gain insight to the molecular processes and to find potential biomarkers in blood samples collected prior to the onset of symptoms of AAV. Methods The National Patient Register and Cause of Death register were searched for AAV-ICD codes and linked to the registers of five biobanks. Eighty-five AAV cases were identified (34 males, 51 females) with samples &gt;1month &lt;10years from AAV symptom onset. For each case two controls matched for sex, age, and sampling date were included. Samples were analyzed using ELISAs for PR3- or MPO-ANCA specificities. Ninety-two protein markers were analyzed using Olink Inflammation panel, (OLINK, Uppsala, Sweden) with 73 eligible after quality control. Results Eight protein markers were significantly altered between pre-AAV and controls, with higher levels of CCL23, CXCL5 (p&lt; 0.01-0.05) and lower levels of Flt3L, STAMBP, ADA, TNFB, CX3CL1 and IL-15RA (p&lt; 0.01-0.05) in the pre-AAV individuals. Nine protein markers were found significantly associated with time to symptom onset; CXCL9, CD244, VEGFA, CXCL1, TNFSF9, OPG, CSF-1, IFN-gamma and CD40 (p&lt; 0.01-0.05). In pre-AAV individuals, six proteins were associated with MPO-ANCA-positivity compared with the MPO-ANCA-negative pre-AAV individuals which showed no overlap with the seven proteins related to PR3-ANCA-positivity. Conclusion To our knowledge our study is the first to analyze for and identify protein markers before symptom onset in AAV. This allowed for further studies of underlying cellular and molecular mechanisms in AAV pathogenesis as well as the diversification into PR3-ANCA and MPO-ANCA subphenotypes. Disclosure of Interests Mikael Brink: None declared, Ewa Berglin: None declared, Aladdin J Mohammad Speakers bureau: Roche, Gsk, AMGEN; Vifor, Lilly, Consultant of: Roche &amp; AMGEN, Andrey Alexeyenko: None declared, Kristina Lejon: None declared, Solbritt Rantapää Dahlqvist: None declared
Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma
Authors: Jason Westin, R. Eric Davis, Lei Feng, Fredrick Hagemeister, Raphael Steiner, Hun Ju Lee, Luis Fayad, Loretta Nastoupil, Sairah Ahmed, Alma Rodriguez, Michelle Fanale, Felipe Samaniego, Swaminathan P. Iyer, Ranjit Nair, Yasuhiro Oki, Nathan Fowler, Michael Wang, Man Chun John Ma, Francisco Vega, Timothy McDonnell, Chelsea Pinnix, Donna Griffith, Yang Lu, Sanjit Tewari, Ryan Sun, David W. Scott, Christopher R. Flowers, Sattva Neelapu, Michael R. Green
Journal: Journal of Clinical Oncology (2022)

Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non-germinal center B-cell-like subset.
Neoadjuvant Chemo–ICI Boosts NSCLC Survival
Journal: Cancer Discovery (2022)

Updated data from the phase II NADIM trials indicate that combining neoadjuvant nivolumab with chemotherapy benefits patients with operable non-small cell lung cancer, boosting rates of pathologic complete response as well as progression-free and overall survival. RNA sequencing may also have uncovered biomarkers that could better pinpoint patients at high risk of disease progression despite treatment.
Dynamics of monocyte-derived macrophage diversity in experimental myocardial infarction
Authors: Giuseppe Rizzo, Julius Gropper, Marie Piollet, Ehsan Vafadarnejad, Anna Rizakou, Sourish Reddy Bandi, Panagiota Arampatzi, Tobias Krammer, Nina DiFabion, Oliver Dietrich, Anahi-Paula Arias-Loza, Marco Prinz, Matthias Mack, Kai Schlepckow, Christian Haass, Jean-Sébastien Silvestre, Alma Zernecke, Antoine-Emmanuel Saliba, Clément Cochain
Journal: Cardiovascular Research (2022)

Abstract Aims Macrophages have a critical and dual role in post-ischaemic cardiac repair, as they can foster both tissue healing and damage. Multiple subsets of tissue resident and monocyte-derived macrophages coexist in the infarcted heart, but their precise identity, temporal dynamics, and the mechanisms regulating their acquisition of discrete states are not fully understood. To address this, we used multi-modal single-cell immune profiling, combined with targeted cell depletion and macrophage fate mapping, to precisely map monocyte/macrophage transitions after experimental myocardial infarction. Methods and results We performed single-cell transcriptomic and cell-surface marker profiling of circulating and cardiac immune cells in mice challenged with acute myocardial infarction, and integrated single-cell transcriptomes obtained before and at 1, 3, 5, 7, and 11 days after infarction. Using complementary strategies of CCR2+ monocyte depletion and fate mapping of tissue resident macrophages, we determined the origin of cardiac macrophage populations. The macrophage landscape of the infarcted heart was dominated by monocyte-derived cells comprising two pro-inflammatory populations defined as Isg15hi and MHCII+Il1b+, alongside non-inflammatory Trem2hi cells. Trem2hi macrophages were observed in the ischaemic area, but not in the remote viable myocardium, and comprised two subpopulations sequentially populating the heart defined as Trem2hiSpp1hi monocyte-to-macrophage intermediates, and fully differentiated Trem2hiGdf15hi macrophages. Cardiac Trem2hi macrophages showed similarities to ‘lipid-associated macrophages’ found in mouse models of metabolic diseases and were observed in the human heart, indicating conserved features of this macrophage state across diseases and species. Ischaemic injury induced a shift of circulating Ly6Chi monocytes towards a Chil3hi state with granulocyte-like features, but the acquisition of the Trem2hi macrophage signature occurred in the ischaemic tissue. In vitro, macrophages acquired features of the Trem2hi signature following apoptotic-cell efferocytosis. Conclusion Our work provides a comprehensive map of monocyte/macrophage transitions in the ischaemic heart, constituting a valuable resource for further investigating how these cells may be harnessed and modulated to promote post-ischaemic heart repair.
POS0018 REDUCTION OF DIFFUSE NOXIOUS INHIBITORY CONTROL IN ACTIVE INFLAMMATORY RHEUMATISM: A DEMONSTRATION OF CENTRAL SENSITISATION
Authors: A. P. Trouvin, A. Simunek, J. Coste, T. Medkour, S. Carvès, D. Bouhassira, S. Perrot
Journal: Annals of the Rheumatic Diseases (2022)

Background In rheumatoid arthritis (RA) and spondyloarthritis (Spa), persistent pain remains challenging. It is thought to result from central pain sensitisation, which can be measured by quantitative sensory testing (QST) and conditioned pain modulation (CPM). Objectives The main objective of the RAPID (Rheumatism Pain Inhibitory Descending pathways) study, was to assess descending pain modulation (through CPM paradigms) in patients with RA or Spa, comparing these patients with healthy sex- and age-matched controls. The secondary objectives were the measurement pain thresholds (heat and cold) in a non-articular, non-painful area in patients and controls as a means of detecting possible widespread hyperalgesia as another index of central sensitisation in our patients. Methods We included 50 RA and 50 Spa patients and 100 age- and sex-matched controls. We assessed clinical disease variables for patients, together with responses to various psychological questionnaires. All participants underwent QST with the determination of heat and cold pain thresholds (HPT-CPT) and CPM. In CPM, a conditioning stimulus was applied to a foot and the non-dominant hand in a randomised sequence. Descending pain control was assessed as the change in HPT (in °C) following a conditioning stimulus: the higher the CPM effect, the more efficient the inhibitory control. Results HPT and CPT were similar in patients and controls. Mean CPM effect was significantly weaker in patients than controls: 0.25°C (±2.57) and 2.79°C (±2.31) for patients and controls, respectively (p&lt;0.0001) for conditioning on the foot; 0.57°C (±2.74) and 2.68°C (±2.12) (p&lt;0.0001), respectively, for conditioning on the hand. The heat pain threshold was 42.35°C (± 3.68°C) for patients and 41.54°C (± 3.34°C) for healthy controls; this difference was not statistically significant. The cold pain threshold was 13.11°C (± 10.04°C) for patients and 13.28°C (± 9.34°C) for healthy controls; this difference was not significant. The weaker CPM effect in patients was associated with higher pain intensity. In all participants, a weak CPM effect was associated with high Central Sensitisation Inventory score, anxiety, depression, sleep disturbance and pain catastrophising. Conclusion Diffuse noxious inhibitory control is weaker in patients with active chronic inflammatory rheumatism than in healthy subjects, supporting the hypothesis of central sensitisation. Figure 1. Disclosure of Interests None declared